Early disease diagnosis, especially in diseases such as cancer, is of central importance to halting disease progression, and reducing morbidity. Diagnostic disease research typically has focused on specific mutations in DNA that result in lost or modified cellular activities. For example, considerable research has focused on DNA mutations associated with cancer. Cancer is a disease thought to be characterized by genomic instability. Generally, genomic instability defines a broad class of disruptions in genomic nucleotide sequences. Numerous genomic instabilities have been associated with cancer. For example, mutations in a number of oncogenes and tumor suppressor genes have been implicated in tumorigenesis. Duffy, Clin. Chem., 41: 1410-1413 (1993). In addition, the loss of heterozygosity at the P53 tumor suppressor locus has been correlated with various types of cancer. Ridanpaa, et al., Path. Res. Pract, 191: 399-402 (1995). The loss or other mutation of the apc and dcc tumor suppressor genes has also been associated with tumor development. Blum, Europ. J. Cancer, 31A: 1369-372 (1995). Finally, tumorigenesis has also been correlated with microsatellite instability. Genetic changes characteristic of genomic instability theoretically can serve as markers for the early stages of, for example, color cancer, and can be detected in DNA isolated from biopsied colonic epithelium and in some cases from transformed cells shed into fecal material. Sidransky, et al., Science, 256: 102-105 (1992).
While DNA-based diagnostics provide useful information concerning genomic disruptions associated with disease, such tests are not necessarily informative with respect to DNA expression. Some researchers have attempted to measure DNA expression by looking for changes in cellular protein content. Increased protein expression results in markers characteristic of various diseases. For example, the protein, prostate-specific antigen, has been used as a diagnostic marker for prostate cancer. Similarly, carcinoemrbyonic antigen has been used as a marker of colorectal cancer. Such protein markers generally are indicative of a late stage in the etiology of the disease. Often, by the time such markers are detected, the associated disease has progressed to a state that is difficult to treat or cure. Accordingly, there is a need in the art for methods for early detection of changes in gene expression that are indicative of disease.